Philip Goldwasser

Predictors of Survival in Continuous Ambulatory Peritoneal Dialysis Patients: The Importance of Prealbumin and Other Nutritional and Metabolic Markers

Serum markers of visceral and somatic protein status are directly correlated with the survival of hemodialysis patients. We prospectively examined the relationship of single baseline levels of serum albumin, cholesterol, creatinine, and urea to prognosis in 80 continuous ambulatory peritoneal dialysis patients monitored for up to 33 months. Other variables tested included age, race, gender, diabetes, cause of end-stage renal disease, and number of months on dialysis. The Cox proportional hazards model was used to determine independent predictors of mortality risk. In a subgroup of 33 patients followed for up to 21 months, the predictive value of single measurements of baseline serum prealbumin also was tested. Overall, 29 patients died during the study. Independent predictors of mortality risk included serum albumin (P = 0.024) and creatinine (P = 0.006), diabetes (P < 0.06), prior months on dialysis (P < 0.05), and older age (P = 0.18). In a subgroup of 33 patients with prealbumin measurements, there were nine deaths over 21 months. A serum prealbumin level less than 30 mg/dL was associated with an increased mortality rate compared with higher prealbumin values (odds ratio, 3.8; P = 0.09). We conclude that markers of visceral and somatic nutrition are important and independent predictors of mortality risk in continuous ambulatory peritoneal dialysis patients. We are unable to suggest whether the relationship is causal or causative. However, the predictive value of these single baseline markers were valid for up to 33 months. We also note that patients with diabetes are at an increased risk even after adjusting for somatic and visceral protein status.

Prealbumin and Lipoprotein(a) in Hemodialysis: Relationships With Patient and Vascular Access Survival

The high morbidity and mortality of hemodialysis patients has led to a search for early markers of risk. Because cardiovascular and nutritional risk are prevalent in this population, we examined the prognostic value of the serum levels of two markers of risk in the general population: (1) lipoprotein(a) [Lp(a)], a low-density lipoprotein-like particle linked to myocardial infarction and coronary bypass stenosis, and (2) prealbumin, a marker of visceral protein status, with a shorter half-life than that of serum albumin. Baseline demographics, clinical information, dialysis prescription, and serum biochemistry measurements of 125 hemodialysis patients followed for up to 14 months were recorded on enrollment. Vascular access events and deaths were recorded prospectively. The hypotheses tested were that increased serum Lp(a) levels would predict cardiovascular mortality and vascular access stenosis and thrombosis, and that reduced serum prealbumin levels would predict mortality risk independently of established risk predictors. Cross-sectional analysis of serum Lp(a) demonstrated a skewed distribution with a median value of 38.3 mg/dL (upper tertile, > or = 57 mg/dL). Lipoprotein(a) was significantly higher in black patients (P < 0.001) and was significantly correlated (P < 0.005) with total cholesterol and apoprotein B (apoB), but not with a history of prior coronary disease. Serum prealbumin was strongly correlated with serum albumin (r = 0.49, P < 0.001). However, prealbumin correlated (P < 0.001) more strongly with other serum nutrition markers (total cholesterol, apoB, creatinine, urea) than did serum albumin. Fourteen-month cumulative survival was 80%. Age, diabetes, and serum levels of albumin, prealbumin, creatinine, total cholesterol and apoB, but not Lp(a), were correlated with survival in univariate analysis. Using the Cox proportional hazards model, independent predictors of mortality risk were prealbumin less than 15 mg/dL versus higher values (relative risk [RR] = 4.48, P < 0.01), apoB (RR = 0.97 per 1 mg/dL increase, P < 0.02), creatinine less than 10 mg/dL versus higher values (RR = 3.51, P = 0.04), and age (RR = 1.04 per year, P = 0.10). Thirty-eight patients experienced at least one vascular access thrombosis (n = 33) or stenosis (n = 5) during the study. Patients with Lp(a) > or = 57 mg/dL had decreased vascular access event-free survival compared with patients with Lp(a) less than 57 mg/dL (56% v 73%, P < 0.06). This trend was increased in magnitude and statistically significant for white and Hispanic patients (31% v 79%, P < 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

The Uremic Dyslipidemia: A Cross-Sectional and Longitudinal Study

Patients on maintenance hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) exhibit numerous disturbances of serum lipids and apoproteins that may contribute to their high cardiovascular mortality. Cross-sectional studies have found that lipid levels are inversely related to time on dialysis. However, it is not known whether this association is the result of the attrition of hyperlipidemic patients or a decrease in lipid levels over time in all patients. Additionally, few studies have investigated the effect of dialysis modality on the lipoprotein disturbances of uremia adjusting for the confounding influences of demographics, or nutritional and endocrine status. To address these issues, we undertook a cross-sectional and longitudinal study of lipids, apoproteins, and atherogenic risk ratios in patients maintained on HD and CAPD. Patients were enrolled in annual cohorts from 1987 to 1990 and monitored until 1991. A total of 196 HD and 77 CAPD patients were studied. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), apoprotein (apo) A-I, and apo B were measured on enrollment and remeasured annually in survivors through 1990. Using multivariate methods, we examined the relationship of the lipids, apoproteins, their respective ratios, and their changes over time, to a broad range of clinical factors and to mortality. Compared with HD patients, CAPD patients had significantly higher TC, apo A-I, and apo B, and a significantly lower apo A-I/apo B ratio. Serum albumin correlated directly with TC and apo B and inversely with apo A-I/apo B. For patients with normal serum albumin (> or = 3.5 g/dL [35 g/L]), CAPD patients had a significantly higher TC/HDL-C than HD patients; otherwise the ratios were similar for CAPD and HD. Independent influences on lipoprotein levels in HD and CAPD patients were also demonstrated for race, gender, and diabetes, but not for parathyroid hormone (PTH) levels. For both dialysis modalities, patients who died had significantly lower TC and apo B, and significantly higher apo A-I/apo B throughout their entire courses compared with survivors. In the subset of patients followed longitudinally for 2 or more years, apo B tended to decrease with time, but TC, HDL-C, and apo A-I were stable. The longitudinal changes in lipoproteins did not correlate with outcome or other factors. In conclusion, CAPD patients have more atherogenic lipoprotein profiles than HD patients. Improved visceral protein nutritional status, as defined by serum albumin level, is associated with hyperlipidemia and, especially vor CAPD, worsened atherogenic risk ratios.(ABSTRACT TRUNCATED AT 400 WORDS)

Correlates of Vascular Access Occlusion in Hemodialysis

Vascular access occlusion results in significant morbidity in hemodialysis patients. Age, diabetes, and synthetic grafts (polytetrafluoroethylene [PTFE]) have been associated with vascular access occlusion in univariate analysis. However, the independent risk associated with each of these factors has not been assessed adjusting for confounding among the factors or by other variables, such as blood pressure (BP) or hematocrit. The influence of serum lipoprotein(a) [Lp(a)] and fibronectin on vascular access occlusion has not been widely studied despite their theoretical or demonstrated importance in vascular bypass occlusion. In a cohort study of 124 hemodialysis patients monitored for up to 14 months, we reported that Lp(a) values in the upper tertile (> or = 57 mg/dL) were associated with vascular access occlusion risk in white and Hispanic patients, but not in black patients. We now report an expanded analysis of this data set to determine the independent correlates of vascular access occlusion. Variables tested included age, race, gender, diabetes, access type (PTFE v endogenous), treatment time, systolic BP, hematocrit, heparin and erythropoietin dosage, and serum levels of Lp(a) and fibronectin. In univariate analysis, access occlusion was associated with age, diabetes, PTFE, Lp(a) > or = 57 mg/dL, serum fibronectin, and reduced BP. The independent correlates of first access occlusion were determined with the Cox proportional hazards model. Since the overall model included a significant race x Lp(a) interaction term, we stratified by race. In black patients, risk correlated directly with PTFE (P < 0.01) and inversely with systolic BP (P < 0.001), whereas for white and Hispanic patients, age (P = 0.04) and Lp(a) > or = 57 mg/dL (P = 0.05) were associated with increased risk. In summary, vascular access occlusion was found to be associated with a number of factors. Important independent correlates were PTFE and lower BP in black patients, and age and serum Lp(a) > or = 57 mg/dL in white and Hispanic patients. Diabetes mellitus and increased serum fibronectin may contribute additional risk.

Race and creatinine excretion in chronic renal insufficiency

Black race and the absence of diabetes are associated with higher levels of serum creatinine in patients with end-stage renal disease. We examined whether these factors have a similar influence on creatinine excretion in men with chronic renal insufficiency. The hypotheses were tested in one sample (group A, n = 35) and the findings replicated in a second, independent sample (group B, n = 66). Creatinine excretion normalized to weight (UCr/kg) was compared by race and diabetic status. UCr/kg and creatinine clearance also were compared with the values predicted by the Cockcroft-Gault (CG) formula (based on the regression equation, UCr/kg = 28 - age/5). In each sample, mean UCr/kg was significantly higher in black patients than in nonblack patients (group A, P = 0.004; group B, P = 0.029), and UCr/kg and creatinine clearance were significantly underestimated by the CG predictions in black patients (group A, P < or = 0.004; group B, P < or = 0.019), but not in nonblack patients. Diabetes did not significantly influence UCr/kg. The analysis also was performed at two age levels (< 50 years or > or = 50 years) using groups A and B combined. For black patients younger than 50 (n = 10), observed UCr/kg (P = 0.059) and creatinine clearance (P = 0.025) exceeded the values predicted by the CG formula; the analysis of nonblack patients younger than 50 years was limited by sample size (n = 1). For patients aged 50 years and older (black, n = 32; nonblack, n = 58), mean UCr/kg was significantly higher in black patients (P = 0.034), and UCr/kg and creatinine clearance were significantly underestimated by the CG predictions in black patients (P < or = 0.002) but not in nonblack patients. In multiple regression analysis of all patients aged 50 years and older, UCr/kg was independently influenced by both race (P < 0.05) and age (P < 0.04) (overall model, multiple R = 0.31; P = 0.012). The prediction equation was UCr/kg (mg/kg) = 23.6 - age/8.3 + 1.9 x race (race = 0 if nonblack; race = 1 if black). We conclude that the creatinine excretion rate was strongly affected by race but not diabetes in men with chronic renal insufficiency. The CG formula significantly underestimated UCr/kg and therefore creatinine clearance in black patients. These findings may reflect differences between black and nonblack subjects in body composition, muscle metabolism, or diet, and the interaction of these factors with chronic renal insufficiency.

Pseudohypernatremia and pseudohyponatremia: a linear correction

BACKGROUND Serum sodium is commonly measured by direct potentiometry (DNa), in blood gas panels, or indirect potentiometry (INa), in metabolic panels run on chemistry analyzers. Abnormal values of the serum non-water fraction interfere with INa, with low values causing pseudohypernatremia (INa > DNa) and high values causing pseudohyponatremia (INa < DNa). Previous attempts to derive a linear correction for the difference between INa and DNa (ΔNa) arising from non-water bias--using serum total protein (TP) or albumin (ALB) to represent the non-water fraction--have yielded inconsistent results, possibly owing to differences in sample inclusion criteria, analytic platforms and statistical approach. METHODS We quantified the effects of TP and ALB on ΔNa in 774 critical care patients with closely timed metabolic and gas panels, adjusting for other known effects. RESULTS ΔNa varied inversely with TP, ALB, and the glucose difference between chemistry and gas panels (ΔGlu), and directly with pH and bicarbonate. The effect of TP on ΔNa was essentially linear, but that of ALB was not; hence, further analysis focused on TP. By multiple linear regression, ΔNa decreased by 0.64 ± 0.06 mEq/L for each 1 g/dL increase in TP, adjusted for ΔGlu, pH, and regression to the mean; the TP effect was slightly steeper (0.69 ± 0.06 mEq/L), when adjusted for bicarbonate instead of pH. CONCLUSIONS For each 1 g/dL rise or fall in TP, clinicians may find it useful to adjust INa by 0.7 mEq/L in the same direction in order to correct INa for non-water bias.

Pseudohypobicarbonatemia Caused by an Endogenous Assay Interferent: A New Entity

Serum total carbon dioxide, measured using a chemistry analyzer, and gas panel-derived plasma bicarbonate, calculated from the pH and partial pressure of carbon dioxide, often are used interchangeably for clinical purposes. When they disagree, there is a tendency to accept total carbon dioxide and discredit gas panel-derived plasma bicarbonate values. We report a patient who, during a 5-month hospitalization, had persistently low total carbon dioxide levels (12.4 ± 2.7 [standard deviation] mEq/L [12.4 ± 2.7 mmol/L]), measured using an enzymatic/photometric assay, and a high anion gap (19.2 ± 3.1 mEq/L [19.2 ± 3.1 mmol/L]), suggesting high-anion-gap metabolic acidosis, but who had gas panel-derived plasma bicarbonate (24.0 ± 0.9 mEq/L [24.0 ± 0.9 mmol/L]) and arterial pH values in the reference range. Organic anion levels in blood and urine were unremarkable. Negative interference with the enzymatic assay by the patients serum was shown by the findings that total carbon dioxide level was 7.0 ± 0.1 mEq/L (7.0 ± 0.1 mmol/L) higher when measured using the electrode-based method than using the enzymatic method (P < 0.01), and the patients serum, but not control serum, altered the reaction kinetics of the enzymatic assay by producing turbidity, resulting in an initial increase in absorbance and a falsely low total carbon dioxide value. The turbidity may have resulted from precipitation of 1 of 2 paraproteins in the patients serum or an endogenous antibody binding with an animal protein included in the assay reagents. In summary, a discrepancy between total carbon dioxide level measured using an enzymatic assay and gas panel-derived plasma bicarbonate level was found to be the result of turbidity caused by an endogenous interferent with the total carbon dioxide assay, a novel artifact. When total carbon dioxide and gas panel-derived plasma bicarbonate values disagree, measurement error in total carbon dioxide level should be considered.

Correlates of long-term survival on hemodialysis

the high mortality of hemodialysis (HD) patients in the United States has prompted an examination of causes and markers of mortality risk [1–15]. the National Cooperative Dialysis study demonstrated reduced morbidity in patients randomized to receive high urea clearances (i.e. treatments designed to maintain low seum urea nitrogen [BUN] levels) in the context of adequate protein intake [6]. Yet, the opposite was found in later cross-sectional studies of HD patients. Increased survival was found to be associated with high BUN and creatinine values [6–12]. Lowrie and Lew reported that one-year mortality risk was increased independently by low albumin, creatinine and cholesterol as well as age and male gender [11]. They also noted that association of diabetes with mortality risk was diminished by statistical adjustment for the serum nutritional profilem, particularly the concentrations of creatinine and albumin [11,12]. We found that single measurements of albumin and creatinine are independent predictors of survival for up two years in both recently-diagnosed and longstanding HD patients even when adequately dialyzed [13]. Whether certain markers are correlated more strongly with short term risk vs long term risk remains to be studied.

Graded interference with the direct potentiometric measurement of sodium by hemoglobin

OBJECTIVES Sodium concentration is measured by either indirect (INa) or direct potentiometry (DNa), on chemistry and gas panels, respectively. A spurious difference between these methods (ΔNa=INa-DNa) can be confusing to the clinician. For example, variation in serum total protein (TP) is well known to selectively interfere with INa. Red cells have been suggested to interfere with DNa, but both positive and negative interference have been reported. In this study, the effect of gas panel hemoglobin (Hb) on ΔNa was examined. METHODS ΔNa was calculated in 772 pairs of closely-timed chemistry and gas panels (median: 4min. apart), retrospectively collected from our critical care units, with 1 pair per patient. Hb was treated as a categorical or continuous variable and tested for linear and non-linear effects, with adjustment for 3 known influences on ΔNa-TP, bicarbonate (tCO2), and the chemistry-gas panel glucose difference (ΔGlu). RESULTS Hb ranged from 3.5 to 22.0g/dL [35-220g/L]. In categorical analysis, ΔNa increased with Hb, and the effect was essentially linear. By simple regression, ΔNa rose 0.06±0.03[SE]mmol/L per 1g/dL [10g/L] increase in Hb (p<0.05), but confounding was suspected because Hb also correlated (p<10-3) with TP, tCO2, and ΔGlu. Using multiple regression to adjust for the confounders, ΔNa rose 0.15±0.03mmol/L per 1g/dL [10g/L] rise in Hb (p<10-6). CONCLUSIONS Increasing Hb spuriously decreases DNa and increases ΔNa. A linear correction for this artifact can reduce the discordance between INa and DNa, promoting their interchangeable use.